From the early part of this century, viruses have been used to treat cancer. The approach has been two-fold; first, to isolate or generate oncolytic viruses that selectively replicate in and kill neoplastic cells, while sparing normal cells. Here investigators initially used wild type viruses, and this approach met with some, albeit, limited success. While oncolysis and slowing of tumor growth occurred with little or no damage to normal tissue, there was no significant alteration in the course of the disease. See, Smith et al., Cancer 9: 1211-1218 (1956), Cassel, W. A. et al., Cancer 18: 863-868 (1965), Webb, H. E. et al., Lancet 1: 1206-1209 (1966). See, also, Kenney, S and Pagano, J. J. Natl. Cancer Inst., vol. 86, no. 16, p.1185 (1994).
More recently, and because of the reoccurrence of disease associated with the limited efficacy of the use of wild type viruses, investigators have resorted to using recombinant viruses that can be delivered at high doses, and that are replication competent in neoplastic but not normal cells. Such viruses are effective oncolytic agents in their own right, and further, can be engineered to carry and express a transgene that enhances the anti neoplastic activity of the virus. An example of this class of viruses is an adenovirus that is mutant in the E1B region of the viral genome. See, U.S. Pat. No. 5,677,178, and Bischoff, J. R., D. H. Kim, A. Williams, C. Heise, S. Horn, M. Muna, L. Ng, J. A. Nye, A. Sampson-Johannes, A. Fattaey, and F. McCormick. 1996, Science. 274:373-6.
It is important to distinguish the use of replication competent viruses, with or without a transgene for treating cancer, from the second approach that investigators have used to treat cancer, which is a non-replicating virus that expresses a transgene. Here the virus is used merely as a vehicle that delivers a transgene which, directly or indirectly, is responsible for killing neoplastic cells. This approach has been, and continues to be the dominant approach of using viruses to treat cancer. It has, however, met with limited success, and it appears to be less efficacious than replicating viruses.
As mentioned above, to avoid damage to normal tissues resulting from the use of high dose viral therapy it is preferred that the virus have a mutation that facilitates its replication, and hence oncolytic activity in tumor cells, but renders it essentially harmless to normal cells. This approach takes advantage of the observation that many of the cell growth regulatory mechanisms that control normal cell growth are inactivated or lost in neoplastic cells, and that these same growth control mechanisms are inactivated by viruses to facilitate viral replication. Thus, the deletion or inactivation of a viral gene that inactivates a particular normal cell growth control mechanism will prevent the virus from replicating in normal cells, but such viruses will replicate in and kill neoplastic cells that lack the particular growth control mechanism.
The use of genetically engineered replication-competent herpes simplex virus-type 1 (HSV-1) has been reported as an anti-tumor agent. See, Martuza et al., Science 252: 854 (1991). Specifically, it was shown that HSV-1 thymidine kinase-deficient mutant, dlsptk, exhibited anti-tumor activity towards human malignant glioma cells in an animal brain tumor model. Unfortunately, the HSV-1 dlsptk virus produced significant encephalitis at the doses required to kill the tumor cells adequately. See, Markert et al., Neurosurgery 32: 597 (1993).
U.S. Pat. No. 5,585,096 describes a mutated, replication-competent herpes simplex virus-type 1 (HSV-1) which contains mutations in two genes, is sensitive to antiviral agents such as acyclovir, is not neurovirulent and does not replicate in non-dividing cells, yet can kill nervous system tumor cells. This herpes simplex virus mutant is incapable of expressing both a functional gamma 34.5 gene product and ribonucleotide reductase.
U.S. Pat. No. 5,728,379 describes a method for killing tumor cells in vivo with a replication competent herpes simples virus by the regulated expression of an essential immediate-early viral gene product.
U.S. Pat. No. 5,804,413 describes cell lines that express complementing levels of certain herpes simplex virus essential immediate early proteins
Although progress has been made in identifying and using viruses for treating disease, particularly cancer, there is obviously still a great need for more effective viruses.
An aspect of the invention is the description of a method for treating unwanted hyperproliferative cell growth in a cell population with an amount of a mutant herpes simplex virus which is lytic to the cells, wherein the virus does not produce a functionally active wild-type ICP0 polypeptide coded for by the IE gene 1.
Another aspect of the invention is the description of a method for treating neoplastic cells which over express Beta-catenin as compared to normal cells of the same histological type with an effective amount of a mutant human herpes simplex virus, wherein the virus does not produce a functionally active wild-type ICP0 polypeptide coded for by the IE gene 1.
A further aspect of the invention is the description of pharmaceutical compositions consisting of a mutant human herpes simplex virus, wherein the virus does not produce a functionally active wild-type ICP0 polypeptide coded for the IE gene 1.
Another aspect of the invention is a method of identifying cells which overexpress Beta-catenin by administering to the cells an effective amount of a mutant human herpes simplex virus, wherein the virus does not produce a functionally active wild-type ICP0 polypeptide coded for the IE gene 1.
These and other aspects of the invention will become apparent upon a full consideration of the disclosure set forth herein.